The long-term objective of this research is to further our understanding of brainstem cellular, molecular, and network mechanisms of REM sleep regulation. Specifically, the goal of this renewal application is to investigate the molecular mechanisms within the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT) and dorsal subcoeruleus nucleus (SubCD) with respect to their roles in homeostatic regulation of REM sleep. The central hypothesis of this proposal is that homeostatic regulation of REM sleep and phasic pontine- wave (P-wave) activity are actively regulated by the interaction between brain-derived neurotrophic factor (BDNF) receptors (tropomyosin-related kinase B [TrkB]) and extracellular signal-regulated kinase1/2 (ERK1/2) signaling in the CCC-PPT and SubCD.
Three specific aims have been designed to systematically test this hypothesis: 1. Test the hypothesis that during selective REM sleep deprivation, increased slow-wave sleep and increased expression of BDNF in the CCC-PPT are critical for the development of homeostatic drive for REM sleep, and under the same conditions, increased BDNF expression in the SubCD is critical for the homeostatic regulation of P-wave activity. This goal will be achieved by measuring homeostatic drive-associated changes in BDNF levels in the CCC-PPT, SubCD, and in a number of control areas at different intensities of increased REM sleep homeostatic drive. 2. Test the hypothesis that the interaction between BDNF TrkB receptors and ERK1/2 signaling in the CCC-PPT is critical for the homeostatic regulation of REM sleep, and that this same interaction in the SubCD is critical for the homeostatic regulation of P-wave activity. To test this hypothesis, at the beginning of a selective REM sleep deprivation period we will apply a BDNF TrkB receptor inhibitor, ERK1/2 activation inhibitor, or vehicle control into either the CCC-PPT or SubCD of rats, in order to block the increased homeostatic drive for REM sleep. 3. Test the hypothesis that, in heterozygous BDNF knockout (BDNF+/-) rats, decreased BDNF production in the CCC-PPT attenuates homeostatic regulation of REM sleep, and decreased BDNF production in the SubCD attenuates homeostatic regulation of P-wave activity. To test this hypothesis, at the beginning of the selective REM sleep deprivation period we will apply BDNF either into the CCC-PPT or SubCD of BDNF+/- rats. All of these experiments will be performed on adult, freely moving rats. We believe that the results of these studies will extend the leading edge of knowledge on the basic neurobiological mechanisms of REM sleep regulation. Also, for the first time, these results will launch a new area of investigation aimed at understanding the localized cellular and molecular mechanisms of homeostatic regulation of individual physiological signs of REM sleep. We believe that the results of these studies will shed light on the neuro-pathological mechanisms of REM sleep homeostatic regulatory dysfunctions in a number of psychiatric and neurological disorders (e.g., endogenous depression, schizophrenia, Alzheimer's, Huntington's, Parkinson's, and stroke), and will help us to design therapeutic interventions to eliminate these dysfunctions.

Public Health Relevance

Deficits in the homeostatic regulation of rapid eye movement (REM) sleep and/or activities of its individual physiological sign generators are associated with a number of neurological and psychiatric disorders, which collectively affect large segments of our population. This research is devoted to understanding the cellular and molecular mechanisms that are involved in the homeostatic regulation of REM sleep and one specific physiological sign of REM sleep, pontine-wave (P-wave) activity. Because very little to nothing is presently known about the cellular and molecular mechanisms that homeostatically regulate REM sleep and P-wave generator activity, this work has the potential to pioneer development of novel therapeutic approaches for REM sleep homeostatic regulation deficits seen in endogenous depression, schizophrenia, stroke, Alzheimer's, Huntington's, and Parkinson's diseases among others.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH059839-16
Application #
8681524
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Vicentic, Aleksandra
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02118
Knapp, Clifford M; Ciraulo, Domenic A; Datta, Subimal (2014) Mechanisms underlying sleep-wake disturbances in alcoholism: focus on the cholinergic pedunculopontine tegmentum. Behav Brain Res 274:291-301
Siwek, Donald F; Knapp, Clifford M; Kaur, Gurcharan et al. (2014) Dorsal subcoeruleus nucleus (SubCD) involvement in context-associated fear memory consolidation. Exp Brain Res 232:1535-45
Datta, Subimal; O'Malley, Matthew W (2013) Fear extinction memory consolidation requires potentiation of pontine-wave activity during REM sleep. J Neurosci 33:4561-9
O'Malley, Matthew W; Fishman, Rachel Lea; Ciraulo, Domenic A et al. (2013) Effect of five-consecutive-day exposure to an anxiogenic stressor on sleep-wake activity in rats. Front Neurol 4:15
Desarnaud, Frank; Macone, Brian W; Datta, Subimal (2011) Activation of extracellular signal-regulated kinase signaling in the pedunculopontine tegmental cells is involved in the maintenance of sleep in rats. J Neurochem 116:577-87
Macone, Brian W; O'Malley, Matthew; Datta, Subimal (2011) Sharing stressful experiences attenuates anxiety-related cognitive and sleep impairments. Behav Brain Res 222:351-6
Datta, Subimal; O'Malley, Matthew W; Patterson, Elissa H (2011) Calcium/calmodulin kinase II in the pedunculopontine tegmental nucleus modulates the initiation and maintenance of wakefulness. J Neurosci 31:17007-16
Datta, Subimal; Desarnaud, Frank (2010) Protein kinase A in the pedunculopontine tegmental nucleus of rat contributes to regulation of rapid eye movement sleep. J Neurosci 30:12263-73
Huang, Max P; Radadia, Kushan; Macone, Brian W et al. (2010) Effects of eszopiclone and zolpidem on sleep-wake behavior, anxiety-like behavior and contextual memory in rats. Behav Brain Res 210:54-66
Datta, Subimal (2010) Cellular and chemical neuroscience of mammalian sleep. Sleep Med 11:431-40

Showing the most recent 10 out of 44 publications